Derivatives of terbutylphenyl-1-amino-4-hydroxybutane their preparation processes and the pharmaceutical compositions containing them

ABSTRACT

##STR1## The present invention concerns (4-substituted phenyl)4-oxy 1-aminobutane of the general formula (I) in which X is a nitrogen atom or &gt;CH--CH, and R is a cyclic substituent chosen from the group comprising a) a xanthic substituent, b) a benzimidazolic substituent, as well as salts and optic isomers of the compounds of formula (I). The invention also concerns processes for obtaining the compounds of formula (I) and pharmaceutical compositions containing, as antihistamine ingredient, at least one compound of formula (I) or one of its salts with a mineral or organic acid.

This invention relates to novel derivatives of phenyloxy butanescarrying in position 1 an amino group, the processes for theirproduction and the pharmaceutical compositions containing them as activeingredients.

The present invention more particularly relates to novel derivatives ofphenyl butane, the butane side-chain of them carrying in position 1 anamino cyclic chain.

This invention specifically relates to novel derivatives of 4-(R₇-phenyl) 4-oxy 1-aminobutanes of general formula I ##STR2## wherein --R₆is selected from the group consisting of HOH, ═O and ##STR3## X is asubstituent selected from the group consisting of >N-- and >CH--NH R₇represents COOH, tertbutyl or ##STR4## and R is a cyclic substituentselected from the group consisting of

a) a xanthic derivative of the formula ##STR5## wherein R₁ and R₂, thesame or different, are a hydrogen or a lower alkyl radical having from 1to 5 carbon atoms in straight or branched chain and

R₃ is a halogenated derivative selected from the group consisting of ahalogenbenzyl group of the formula ##STR6## wherein Z is a halogen atomand an ethoxyethyl radical (CH₂ CH₂ OC₂ H₅) and

b) a benzimidazolic derivative of general formula ##STR7## wherein R₄ isa hydrogen or a halogen atom and

R₅ is a halogenobenzyl group ##STR8## wherein Z is a halogen or anethoxyethyl radical.

Among the compounds of general formula I it may then be cited the twofollowing sub-groups:

1. the compounds of general formula I_(A) wherein R is a xanthyl group,selected from the group consisting of piperazinyl xanthines of generalformula I_(A') ##STR9## wherein R is xanthyl group define as previouslyand the piperidyl amino xanthines of general formula I_(A") ##STR10##wherein R is a xanthyl group defined as previously.

2. the compounds of general formula I_(B) wherein R is a benzimidazolicgroup selected from the group consisting of piperazinyl benzimidazolesof general formula I_(B') ##STR11## wherein R₄, R₅, R₆ and R₇ have theabove-given definitions and the piperidylamino benzimidazoles of formulaI_(B") ##STR12## wherein R₄, R₅, R₆ and R₇ are defined as previouslygiven.

Among those compounds of formula I, the most preferred ones are thosefor which R₇ is a tertbutyl radical and namely the compounds of generalformula I_(B) wherein R is a benzimidazolic group such as thepiperazinyl benzimidazoles of formula I_(B') ##STR13## wherein R₄ and R₅are defined as previously-indicated and the piperazinyl benzimidazolesof formula I_(B") ##STR14## wherein R₄ and R₅ have the previously-givendefinition. Generally-speaking the presently preferred compounds arefurther those for which R₅ is a fluorobenzyl radical and R₆ is a hydroxyradical.

This invention also relates to the acid addition salts of a compound offormula I with a mineral or organic acid, preferably atherapeutically-compatible acid.

Those which cannot be used in therapy, such as the iodates, periodates,reineckates or picrates, are utilized as a mean for isolating, purifyingor characterizing these compounds.

Moreover the compounds of general formula I include at least oneasymmetric carbon and consequently may be resolved into their opticalisomers, namely by salification using a chiral acid such asd-camphosulphonic acid, d-dibenzoyltartaric acid, NN-diethyl d-tartramicacid or d-glucose 1-phosphoric acid.

The compounds of general formula I may also be resolved into theiroptically-active isomers by acylating first by means of anoptically-active acid such as 1-methoxy acetic then with mildsaponification. It is further possible to resolve these esters byenzymatic hydrolysis or through chromatography on a column loaded with achiral absorbant.

The present invention further relates to a process for producing thecompounds of formula I which consists in that

for the xanthic derivatives of formula I, a halogeno xanthine having theformula II ##STR15## wherein R₁ and R₂ are defined as previously givenand

Hal is a chlorine or bromine

is let to react with a halogenated derivative selected from the groupconsisting of a benzylic halide having the formula III ##STR16## and anethoxyethyl halide of formula III'

    CH.sub.3 CH.sub.2 OCH.sub.2 CH.sub.2 Hal                   (III')

wherein

Hal means a chlorine or bromine, and

Z is a halogen atom

to obtain a xanthic derivative of general formula IV ##STR17## whereinR₁, R₂ and R₅ are defined as previously-given

then reacts the latter with a 4-(4-R₇ -phenyl) 4-oxy 1-aminobutylderivative of general formula V ##STR18## wherein X, is defined asabove-given

R₆ and R₇ have the above-given definitions and

R is a xanthyl group

to produce a compound of formula I_(A").

When X is equal to >N-- and R to xanthyl, the compound of formula I_(A')may further be produced by condensing a 4-halogeno 1-(R₇ -phenyl)butylderivative of general formula VI ##STR19## wherein R₆ and R₇ have theabove-given definitions and

Hal is a bromine or chlorine

with a N-Xanthyl piperzine of formula VII ##STR20## wherein R₁, R₂, R₃have the above-given definitions.

This reaction is preferably performed in a solvent selected from thecyclic ethers and the alkanols having up to 3 carbon atoms in straightor branched chain, at the reflux temperature of the selected solvent(ether or alkanol) for 2 to 12 hours. A compound of formula I_(A') isthus obtained ##STR21## wherein R₁, R₂, R₃, R₆ and R₇ have theabove-given definitions.

When X is equal to >CH--NH--, the corresponding compound of formula V isprepared by condensing a derivative of general formula VI defined aspreviously with a 4-oximino piperidine of formula VIII ##STR22##

This reaction preferably is carried out in a solvent selected among thealkanols having up to 3 carbon atoms in straight or branched chain, inthe presence of an alkaline agent such as an alkali metal carbonate, atthe reflux temperature of the selected alkanol, for 8 to 12 hours.

A derivative of formula IX is thus obtained ##STR23## wherein R₆ is ahydroxyl and R₇ has the above-given meanings.

The oximino derivative IX is further reduced into a primary amine in amedium consisting of an alkanol having up to 3 carbon atoms in straightor branched chain, by means of an alkali metal at a temperature selectedfrom 20° and the reflux temperature of the alkanol, during from 2 to 12hours depending on the used temperature.

The aminated derivative of formula X is thus obtained ##STR24## whereinR₇ has the above-given definition which is condensed with a compound ofgeneral formula IV to produce a compound of formula I_(A") ##STR25##wherein R₁, R₂, R₅ and R₇ have the above-given definitions.

This reaction is preferably performed in a solvent selected from thealkanols having from 1 to 5 carbon atoms in straight or branched chainand the polar solvents in the presence of an alkaline agent, an alkalimetal carbonate, an earth-alkali metal carbonate, and in the presence ofa catalyst such as an alkali-metal iodide. The carbonates may be thoseof calcium, sodium or potassium. The reaction is carried out at thereflux of the selected solvent, for a set of time which may range from 4to 30 hours depending on the experimental conditions.

They are thus obtained the derivatives of general formula I_(A) whereinthe cyclic amino group is a Xanthyl piperidyl amino or piperazinylgrouping. They may be further converted into the corresponding ketones(R₆ ═O) by means of a metallic oxydizing agent.

These new compounds corresponding to the general formula I_(A') andI_(A") which have thus been produced, may be salified by adding amineral or organic acid, preferably a therapeutically-compatible acid,to obtain the corresponding acid addition salts. These salts also arepart of the present invention.

Mainly as acids which may be used for forming the acid addition salts,it may be cited as an example, the hydrochloric, hydrobromic, sulphuric,phosphoric, acetic, propionic, maleic, fumaric, citric, benzoic andmetane sulphonic acids.

These new compounds of general formula I_(A) are purified, when and ifnecessary, by means of physical or chemical methods such as byrecrystallization or by chromatography.

These compounds have been identified and controlled for the purpose ofpharmacological studies, by means of known analysis methods such aselementary analysis, infra-red spectrophotometry, ultra-violetspectrophotometry, Nuclear Magnetic Resonance (NMR), or high performanceliquid chromatrography (HPLC).

When R is a benzimidazolyl group, the compounds of general formula I inwhich R is the said benzimidazolyl group and X is an amino >N-- group,are produced by condensing an halogenated benzimidazole of generalformula XI ##STR26## wherein R₄ is defined as above-given and

Hal means a chlorine or bromine atom

with a halogenated derivative selected from the group consisting ofbenzylic derivative of formula III ##STR27## and ethoxyethyl halides offormula III'

    CH.sub.3 CH.sub.2 OCH.sub.2 CH.sub.2 Hal

wherein

Hal means a chlorine or bromine and

Z is a halogen atom

to produce a halogenated benzimidazole having the general formula XII##STR28## wherein R₄ has the above-given definitions and particularlychlorine or hydrogen.

The compound of formula XII is reacted with piperazine in a mediumconsisting of a solvent selected among the aromatic hydrocarbons and thesubstituted aromatic hydrocarbons. The preferred solvents are benzene,toluene and the xylenes. It may be of advantage to perform the reactionat a temperature ranging between 40° C. and the boiling point of thesolvent for set of time ranging from 4 to 24 hours, depending on theused temperature.

A benzimidazolic derivative of general formula XIII is thus produced##STR29## wherein --R₄ means hydrogen or chlorine and

R₅ has the previously-given meanings

which is reacted with a 4-halogeno 1-(4-R₇ -phenyl)butane of formula VI##STR30## wherein Hal means a chlorine or bromine and

R₆ and R₇ have the above-given definitions

to produce a compound having the general formula I_(B') ##STR31##

SCHEME OF SYNTHESIS FOR THE BENZIMIDAZOLIC DERIVATIVES I_(B) (X=>CH--NHand R=benzimidazolyl) First Step

Compounds of general formula I_(B") are produced according to the methodwhich consists in reacting a o.nitroaniline of formula ##STR32## with ahalogenated derivative selected from the group consisting of ahalogenated benzylic derivative of formula III ##STR33## and ethoxyethylhalides of formula

    Hal CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3

wherein

Z has the above-given meaning and

Hal is a chlorine or a bromine

to produce an o.nitroaniline of the formula III' ##STR34##

Second Step

reducing the nitro o.phenylenediamine to produce the corresponding amineof formula XVI ##STR35##

Third Step

from a compound of formula X, a tetrahydropyranylated of derivative offormula XIV ##STR36## is prepared wherein the hydroxyl alcoholicfunction is blocked by the group tetrahydropyran.

Fourth Step

formation of the thiocyanate of formula XV by action of carbondisulphide in sodic medium on the tetrahydropyranylated of derivativeXIV ##STR37##

Fifth Step

condensing the benzylamine of formula XVI with the thiocyanate offormula XV to produce a thiourea of formula XVII ##STR38##

Sixth Step

cyclizing in an aromatic hydrocarbon in the presence of a desulphurizingagent to produce a benzimidazolic derivative of formula XVIII ##STR39##

Second Step

hydrolyzing in acidic medium the tetrahydropyranyl ether under very mildconditions to obtain a benzimidazolic derivative of formula I_(B")wherein X=>C═NH ##STR40##

The compounds of general formula I which bear a benzimidazolicsubstituent, of general formula I_(B) et I_(B"), thus obtained, may be:metalic oxidizing reagent, or salified by adding a mineral or organicacid, or purified using the same methods as above for the xanthicderiviatives, or identified and controlled for the purpose ofpharmacological studies, using the same techniques as previouslydescribed.

The compounds of formula I are endowed with interesting pharmacologicalproperties, namely anti-histaminic and anti-allergic properties.Particularly the compounds of general formula I_(B) in which R is abenzimidazole ring, and their acid addition salts with a mineral ororganic, therapeutically-tolerable, acid, namely display anti-histaminicproperties by action on the H₁ -receptors which are of the same typethan that encountered with ASTEMIZOLE.

The compounds of general formula I find hence a use in therapy, mainlyin the allergic states and in the treatment of asthma.

This invention also relates to pharmaceutical compositions including asactive ingredient one derivative of general formula I or aphysiologically tolerable acid addition salt thereof, in admixture orconjunction with a suitable pharmaceutical carrier.

The thus produced pharmaceutical compositions are advantageously offeredin the various forms suitable for the oral, way such as for exampletablets, dragees, soft gelatine, capsules, or preparations suitable forthe administration for the nasal, injectibles ophthalmic, drinkable waysas well as in the form of aerosol, or by rectal way.

The unit dosology may range from 1 to 20 mg per unit dosage. The dailydosage will vary between 1 and 100 mg in the adult man.

The following examples are given as an illustration of the invention anddo not limit it.

The melting points--unless the contrary is mentioned--have beendetermined using a Mettler apparatus. The infra-red spectras aredetermined with a Perkin Elmer Spectrophotometer 1600 serial FTIR. TheUV spectrums are measured using a Kontron spectrophotometer type UVIKON860. The determination by HPLC have been performed with a WatersApparatus type 600 E, fitted with an integrator APC 4.

EXAMPLE I 1,3-dimethyl 7-(4-fluorophenyl) 8-[1-(4-tertbutylphenyl)4-hydroxybutyl 4-piperidyl amino] Xanthine (I_(A) ") Step A:Hydroxyamino Piperidine

46.2 g of piperidine 4-one as the hydrochloride are heated at the refluxtemperature under stirring with 38.4 g hydroylamine hydrochloride in 250ml ethanol in the presence of 100 g sodium carbonate. After 3 hoursreflux, the resulting suspension is filtered and the solid is washedfour times with 100 ml boiling ethanol. The ethanolic solution isconcentrated under vacuum. The solid residue is taken up in methylenechloride, filtered on a clay (Trade mark Celite®), and concentrated anew to dryness. 34.1 g of a colourless product are obtained which meltsat 117.2° C. In TLC it is mono-spot in a system formed with methanol100/ammonia 2, on plates of silica MERCK and staining with CuCl₂/ninhydrin.

Step B: 1-[4-tertbutyl phenyl) 4-hydroxy 1-butyl] 4-hydroxyiminopiperidine

A mixture of 11.4 g 4-oximinopiperidine of step A, 24 g of 4-chloro4-(4-terbutyl phenyl) 1-butanol and 100 g sodium carbonate in 100 mlethanol are heated at reflux for 8 hours under stirring. After this setof time, the solvent is concentrated under reduced pressure. The dryresidue is taken up after cooling with water to eliminate the mineralsalts. The product is extracted with methylene chloride and after dryingon sodium sulphate and after the solvent is eliminated in vacuum, theproduct is recrystallized from isopropyl ether to recover 27 g of purecompound as colourless crystals. Melting point 128.5°-131° C.

Step C: 1,3-dimethyl 7-(4-fluorobenzyl) 8-chloroxanthine

A solution of 43 g 1,3-dimethyl 8-chloro xanthine in 200 ml water and 20ml sodium hydroxide 10N is heated to 70°-80° C., to which 27.6 ml4-fluorobenzyl chloride are portion-wise added at this temperaturewithin 4 hours. During this addition, 20 ml sodium hydroxide 10N areadded by small portions to maintain the pH at an alkaline value. Afterachievement of this addition, the solution is further heated at 70°-80°for 2 hours then let to revert to room temperature under stirring. Theprecipitate is filtered, dried, washed with water until neutral, thendried. Thereafter it is recrystallized from acetone to recover 19 g ofpure compound. It melts at 183°-184° C.

Step D: 1-4[(4-tertbutylphenyl) 4-hydroxy] 1-butyl 4-amino piperidine

A solution of 25.5 g of the oxime of step A in ethanol (previously driedon a molecular sieve 4A for a night), is reduced using metallic sodiumat the reflux when all the metallic sodium has disappeared (23.5 g),boiling is maintained for 1 hour then the solution is cooled undernitrogen. A solution of 57 g ClH 4N in 200 ml water is added and ethanolis evaporated off at the maximum possible.

The thus-formed amine is extracted with n-butanol and after washing withwater it is concentrated to dryness under vacuum. Its dry residue istaken up in methylene chloride, dried on sodium sulphate, filter andconcentrated to dryness. The raw product is recrystallized from amixture hexane (100 p)-methanol (1p)-13.3 g of the compound arethus-obtained. The derivative melts at 99.2° C.

Step E: 1,3-dimethyl 7-(4-fluorobenzyl) 8-[1-(4-tertbutyl phenyl)4-hydroxybutyl-4 piperidyl)amino] Xanthine (I_(A"))

A mixture of 32 g 8-chloro 7-(4-fluorobenzyl) theophylline, 16 g sodiumiodide, 30 g 1-[(4-tertbutyl phenyl) 4-hydroxy]butyl-4 amino piperidine,12 g sodium carbonate and 200 ml dimethyl formamide is heated at thereflux under nitrogen atmosphere for 24 hours.

After cooling, the suspension is poured into 800 ml iced water, theprecipitate is filtered and dried, then washed until neutral. The rawproduct is purified by chromotography on alumina column, washing withhexane then with isopropyl ether and finally with acetone. After havingconcentrated the acetonic phase, 17.6 g of solid product are recoveredwhich are further recrystallized from a mixture of hexane (3p) andacetone (1p). Melting point: 95° C.

    ______________________________________                                        Analysis C.sub.33 H.sub.43 N.sub.6 O.sub.3 F                                             C    H          N      F%                                          ______________________________________                                        Theoretical  67.09  7.3        14.22                                                                              3.22                                      Found        67.10  7.27       14.03                                                                              3.18                                      ______________________________________                                    

UV (MeOH) χ max in nm: 296 and 216.2

IR (BrK) in cm⁻¹, 1224, 1625, 1640, 1605, 3330, 3400

NMR ¹ [H] Spectrum in CDCl₃ : (internal ref. TMS, δ in ppm): 1.3 (s, 9Hof tertbutyl) 3.38 (s, 3H of N--CH₃) 3.52 (s, 3H of N--CH₃) 4.60 (td,1H, CH--O) 7-7.40 (m, 8H aromatics)

Hydrochloride: MP=167°-169°

Furmarate: MP=179°

EXAMPLE II 1,3-dimethyl 7-(4-fluorophenyl) 8-[4-(4-tertbutylphenyl)4-hydroxybutyl)piperazinyl] Xanthine (I_(A')) Step A:1-[(4-tertbutylphenyl) 4-hydroxyl] butyl piperazine

6.36 g piperazine as the anhydrous base are dissolved in 19 ml ethanolat 20° C. When the whole piperazine is dissolved, 8.90 g of 4-chloro1-[4-(tertbutylphenyl)] 1-butanol are added at once.

The mixtures is heated at 80° C. for 6 hours then let to revert at 20°C. and the reaction mixture is extracted with isopropyl ether. The rawproduct is thereafter recrystallized from ethyl acetate. 6 g of purecompound are recovered. MP=114°-115° C.

Step B: 1,3-dimethyl 7-(4-fluorobenzyl) 8-[4-(4-tertbutylphenyl)4-hydroxy)butyl piperazinyl] Xanthine

A mixture of 16.53 g 7-(4-fluorobenzyl) 8-chloro theophylline and 14.86g of 1-[4-(4-tertbutylphenyl) 4-hydroxy]butyl piperazine in 100 ml dryethanol is prepared, then heated to 80° C. for 9 hours. Aftertermination of the reaction, ethanol is concentrated under vacuum andthe resulting product extracted with methylene chloride. Afterrecrystallization in 1 vol ethanol and 2 vol isopropyl ether, 6 g ofpure compound are recovered. MP=145° C.

    ______________________________________                                        Analysis C.sub.32 H.sub.41 N.sub.6 O.sub.3 F                                             C    H          N      F%                                          ______________________________________                                        Theoretical  66.63  7.11       14.57                                                                              3.29                                      Found        66.24  7.08       14.53                                                                              3.65                                      ______________________________________                                    

UV (dry ethanol) χ max in nm=291.6 and 205.8

IR (KBr): ν cm⁻¹ : 1222, 1440, 1510, 1660, 1700, 3180

NMR ¹ [H] (in CDCl₃, intern. Ref. TMS, δ in ppm): 1.3 (s, 9H oftertbutyl) 3.35 (s, 3H, N=CH₃) 3.52 (, 3H, N=CH₃) 4.65 (ex 1H, --CHO)6.9-7.40 (m, 8H aromatics)

Hydrochloride: MP=202°-204° C.

Furmarate: MP=88°-89°

EXAMPLE III 1-(4-fluorobenzyl) 2-[4-(4-tertbutylphenyl)4-hydroxybutyl)piperazino] benzimidazole (I_(B')) Step A:2-chlorobenzimidazole

A solution of 2-hydroxy benzimidazole (40.2 g) in 93 ml phosphorusoxychloride is heated to reflux under stirring for 6 hours. Afterachievement of the reaction the solution is let to revert to -10° C. andhydrolysed with 100 g crushed ice and 100 ml iced water. They are slowlyadded 249 ml sodium hydroxide 10N to get a neutral pH value. Theprecipitated product is filtered, washed with the minimal amount ofwater. The crystals are taken up in hot ethanol. After cooling, thealcoholic juice are filtered and concentrated to dryness.

Step B: 2-chloro 1-(4 fluorobenzyl) benzimidazole

11 g 2-chlorobenzimidazole are dissolved in 74 ml water and 17.35 ml 30%sodium hydroxide. The mixture is heated to 82° C. and to this they areslowly added 23.76 g 4-fluorobenzyl chloride within 5 hours. When thereaction is achieved, the solution is cooled to 20° C. and extractedwith methylene chloride. The compound is recrystallized from ethylacetate.

Step C; 1-(4-fluorobenzyl) 2-piperazinyl benzimidazole

In 168 ml xylene 40.8 g anhydrous piperazine and 60 g 2-chloro(4-fluorobenzyl) benzimidazole are added. The mixture is heated to 80°C. for 10 hours. When the reaction is no longer evoluting, thetemperature is reverted to 20° C. and the pH value is adjusted to 2 withan aqueous solution of hydorchloric acid at 30%. The organic solution iswashed with water then the pH is increased to pH 11 with sodiumcarbonate. The compound is extracted with isopropyl ether. Finally 46 gpure compound are recovered.

Step D: 1-(4-fluorobenzyl) 2-[4-(4-tertbutylphenyl) 4-hydroxybutyl)piperazino] benzimidazole

In 80 ml n-butanol they are mixed 28.45 g 2-chloro 1-(4-fluorobenzyl)benzimidazole, 9.7 g sodium carbonate, 13.66 g sodium iodide and 30 g4-chloro 1-(4-tertbutyl phenyl) 1-tetrahydropyranyloxy butane. Thesolution is heated to 100° C. for 16 hours. When the reaction isachieved, the compound is extracted with isopropyl ether; the organicphase is washed to neutral then concentrated to dryness. The alcoholicfunction is freed by hydrolysis with a solution of by hydrochloric acidat 0.6% for 45 mn. The compound is anew extracted with ether,neutralized with sodium carbonate and recrystallized from isopropylether with a minimal amount of ethanol. They are finally obtained 19.90g of pure compound melting at 179.2° C.

    ______________________________________                                        Analysis C.sub.33 H.sub.39 N.sub.4 OF                                                    C    H          N      F%                                          ______________________________________                                        Theoretical  74.70  7.58       10.89                                                                              3.69                                      Found        73.57  7.73       10.71                                                                              3.66                                      ______________________________________                                    

UV (MeOH) χ max in nm: 285.6 and 248.8 213

IR (BrK) in cm⁻¹ : 954, 1080, 1129, 1609, 3222

NMR ¹ [H] Spectrum in CDCl₃ : (internal ref. TMS, δ in ppm): 1.3 (s, 9Hof tertbutyl) 4.65 (td, 1H, --CHO) 5.15 (s, 2H, CH₂ benzylic) 6.9-7.65(m, 12H aromatics)

Hydrochloride: MP=173°-175.5° C.

Fumarate: MP=196°-197°

EXAMPLE IV 1-(4-fluorobenzyl) 2-[4-(tertbutylphenyl) 4-hydroxybutyl)4-piperidyl) amino] benzimidazole (I_(B")) Step A: 1-chloro(4-tertbutylphenyl) butanaol

200 g 1-chloro (4-tertbutylphenyl) 3-butanone are dissolved in 1680 mlmethanol, then a solution of 16.78 g sodium borohydride in 151 ml waterand 1.31 g sodium hydroxide are added thereto within 30 mn. Thetemperature of the reaction mixture is kept between 10° and 20° C.during addition of sodium borohydride. It is kept under stirring for 5hours then the methanolic solution is concentrated under vacuum. Themedium is extracted with isopropyl ether and the compound isrecrystallized from 2 vol hexane. 183 g of pure compound are recovered.Its melting point is 50.9°-51.3° C.

Step B: 1-chloro 1-[4-tertbutylphenyl] 4-tetrahydropyranyloxy butane

In 8.7 ml dihydropyran they are added 10 mg p.toluene sulphonic acid(APTS). To this mixture they are added within 30 mn at 60°, 20 g1-chloro (4-tertbutylphenyl) butanol. After this addition the mixture isstill heated at between 60° and 65° C. for 30 mn and kept under stirringfor further 90 mn. 0.5 g sodium bicarbonate is thereafter added. Themixture is then stirred for 1 hour. The tetrahydropyranylated derivativeis directly used without any further purification.

Step C: N-(4-fluorobenzyl) phenylene diamine

56 g N-(4-fluorobenzyl) 2-nitroaniline are reduced in the presence of 34g of 5% palladized charcoal into methanol (560 ml) using a stream ofhydrogen at room temperature and normal pression. After achievement ofthe reaction, the mixture is washed with nitrogen, filtered on clay(Trade Mark Celite) and concentrated to dryness. The residue isrecrystallized from isopropyl ether. The desired N-substituted phenylenediamine, is thus obtained recovered weight: 38.5 g. The startingmaterial N-(4-fluorobenzyl) 2-nitroaniline is prepared by alkylating the2-nitroaniline by means of 4-fluorobenzyl chloride in the methyl ethylketone.

Step D: 1-[(4-tertbutylphenyl) 4-tetrahydro pyranyloxybutyl]4-hydroxyimino piperidine

58.4 g of 1-chloro 1-(4-tertbutylphenyl) 1-tetrahydro pyranyloxy butanein 200 ml ethanol are heated to reflux under stirring with 20 g4-hydroxyimino piperidine and 20 g sodium carbonate. After 20 hoursreflux, the solution is concentrated to dryness then taken up withwater, extracted with dried methylene chloride and concentrated todryness under vacuum 70.5 g of pure compound are thus produced. It isrecrystallized from methanol to recover 40 g of a solid having a meltingpoint of 150°-151° C.

Step E: 1-[(4-tertbutylphenyl) 4-tetrahydropyranyloxy butyl] 4-aminopiperdine

In a 1 l reactor, a solution of the corresponding oxime (35 g in 235 mlethanol) is heated to reflux with 25.5 g sodium for reduction during 1hour. After complete disappearance of the sodium the whole mixture isheated to reflux for 1/2 hour then cooled under nitrogen. They isintroduced in the medium under stirring a solution of 60 g ammoniumchloride in 250 ml water. It is extracted with isopropyl ether, theorganic phase is washed with water, dried on sodium sulphate thenconcentrated to dryness. The residue is purified by recrystallizationfrom methanol to eliminate the not yet reduced, optionally presentoxime. The raw amine after concentration of the methanol, is purified bypassing through a column filled with silica dispersed with hexane theneluted with methanol and the eluate is concentrated to dryness. 25 g ofa compound are recovered as a thick oil.

Step F: 1-[(4-tertbutylphenyl) 4-tetrahydropyranyl oxybutyl)]isothiocyanatopiperidine

In a 250 ml reactor they are put together 10 ml 10N sodium hydroxide and50 ml water than after cooling to 5° C., they are added 6 ml carbonsulphide. A solution of 19.5 g of the amine of the preceding step E in100 ml water and acetic acid is introduced thereto, within 1 hourbetween 0° and 20° C. and the pH value is adjusted to 7-8. The mixtureis stirred for further 2 hours between 0° and 10° C. The disappearanceof the amine is followed through TLC on silica in a mixture of CHCl₃/ethanol (7:3). The mixture is warmed to 20° C. and to the latter 10 mlethyl chlorocarbonate are poured dropwise without passing 30° C. within3/4 hour. The whole mixture is heated for 2-3 hours at 50°-60° C. on thewater-bath until cessation of the staining into brown, of a paperimpregnated with lead acetate. (TLC on SiO₂ with cyclohexane 3-ethylacetate 7). After cooling the solution is extracted with methylenechloride, washed, dried and concentrated to dryness. The product ispurified on a column of silice dispersed with hexane and elution with amixture of cyclohexane-5 ethyl acetate 5-15.3 g of a viscous product arethus obtained.

Step G: N-[1-(4-tertbutylphenyl) 5-tetrahydropyranyl) piperadinyl]oxybutyl]N-[2-(4-fluorobenzyl amino phenyl] Thio Urea

In 150 ml methanol they are mixed 25.4 g 1-[4-tertbutylphenyl)4-tetrahydropyranyl oxybutyl] 4-isocyanatopiperidine and 18.3 gN-(4-fluorobenzyl) 1,2-phenylene diamine and this mixture is kept asidefor 24 hours. It is thereafter concentrated to dryness under vacuum andthe residue is passed through a column filled with silica dispersed withcyclohexane, to eliminate the excess of aromatic amine. The resultingthiourea is extracted with ethyl acetate. 33 g of an oily compound arethus obtained.

Step H: 1-(4-fluorobenzyl) 2-4-tertbutylphenyl) 4-hydroxybutyl4-piperidinyl amino] benzimidazole

They are heated to reflux into 200 ml benzene, 33 g of the thioureaobtained in the step G, together with 16 g dicyclohexyl carbodiimide for5 hours. After achievement of the reaction, it is cooled, washed withwater than with an aqueous solution of sodium carbonate and further withwater. It is dried and concentrated to dryness under vacuum, the residueis taken up with 100 ml methanol and 20 ml water, then the pH value isadjusted to 1 with concentrated hydrochloric acid. The end of thereaction is followed by TLC on silica plates with chloroform 7--ethanol3 (revelation UV and Iodoplatinate). It is neutralized after dilutionwith water using sodium carbonate then sodium hydroxide to obtain a pHvalue of 12. It is extracted with methylene chloride, the organicsolution is washed with water, dried, filtered and concentrated todryness. 37 g of raw product are produced which are washed withisopropyl ether and 24 g of the pure compound are obtained. The productis recrystallized from ethyl acetate containing a little methanol.MP=164.8°165.2° C.

    ______________________________________                                        Analysis C.sub.33 H.sub.41 N.sub.4 OF                                                    C    H          N      F%                                          ______________________________________                                        Theoretical  74.96  7.82       10.60                                                                              3.59                                      Found        73.80  7.80       10.30                                                                              3.50                                      ______________________________________                                    

UV (MeOH) χ max in nm: 286.2-249.4 and 18.4

IR (BrK) in cm⁻¹ : 1087, 1227, 1570, 1616, 3068, 3227

NMR ¹ [H] (CDCl₃, internal ref. TMS, δ in ppm): 1.3 (s, 9H of tertbutyl)4.02 (td, 1H, --CHO) 5.03 (s, 2H, CH₂ benzylic) 6.90-7.55 (m, 12Haromatics)

Hydrochloride: 204°206° C.

Fumarate: 177°

EXAMPLE V Examples of Realization of Pharmaceutical Formulations

    ______________________________________                                        A - Soft gelatine capsules                                                    Active ingredient         20       g                                          Lactose                   100      g                                          Microcrystalline Cellulose                                                                              23       g                                          Magnesium stearate        1        g                                          Colloidal silica          1        g                                          enough for 1000 soft gelatine capsules                                        B - Tablets                                                                   Active ingredient         50       g                                          Lactose for compression   1360     g                                          Avicel PH 101             200      g                                          Precirol                  20       g                                          Colloidal silica          20       g                                          enough for 10,000 tablets                                                     C - Drinkable solution                                                        Active ingredient         150      mg                                         Preservative agents       1        mg                                         Sorbitol (70% solution)   50       g                                          Alcool at 95%             20       g                                          Purified water enough for 150      g                                          D - Injectible                                                                Active ingredient (in the form of a salt) as a base                                                     1        mg                                         Sodium chloride           5        mg                                         Mono sodium phosphate enough for pH                                                                     5.5-6                                               purified water for injection enough, for                                                                5        ml                                         E - Suppositories                                                             Active ingredient         2.5      mg                                         Whitepsol H35 and H37 (50:50) enough for                                                                3        g                                          F - Aerosols                                                                  Active ingredient         3%                                                  Sorbitol trioleate        2 to 2.5%                                           Propelling agent enough for                                                                             100%                                                G - Eye drops                                                                 Active ingredient in the form of its hydrochloride                                                      1        mg                                         Benzalkonium chloride     0,00125  mg                                         purified water enough for 5        ml                                         ______________________________________                                    

PHARMACOLOGICAL STUDY OF THE COMPOUNDS ACCORDING TO THIS INVENTION

The pharmacological studies of the compounds according to this inventionhave included two aspects: characterization of the main activity ofanti-histaminic H1 type and search of optional undesirable side-effectson the Central Nervous System (CNS). Each of these two sides couldutilize as well "in vitro" techniques for measuring the affinity forspecific receptors or studies on an isolated organ as models of "invivo" pharmacological properties.

I--Characterization of the Anti H1 Activity 1.1 Measurement of theAffinity for the Receptors H1

Increasing concentrations of the compounds to be studied are incubatedwith membranar preparations of homogenates of rat cortexes or guinea piglungs in the presence of a specific ligand of the H1 receptors:Mepyramine labelled with Tritium, at the fixed concentration 2 nM. After30 mn at 25° C. and at pH 7.4, in a 50 mM TRIS-ClH buffer for themembrans of the cortex or a 0.5 M PO₄ HNa₂ /PO₄ H₂ K buffer for thelungs membrans, the residual bound fraction of tritiated ligand iscounted by scintillation in a liquid medium after filtration on anapparatur of the Brandel's type and several washings. The relationshipbetween concentration of the compound to be studied and inhibition ofthe specific binding of tritiated Mepyramine to the H1 receptors, allowsthe calculation of the 50% inhibitory concentration (CI₅₀).

Under these experimental conditions, the compound of example III shows aCl₅₀ of 1.1×10⁻⁶ M on the H1 receptors of rat cortexes and 2.7×10⁻⁶ M onthe H1-receptors of guinea pigs lungs, against respectively 1×10⁻⁶ M and10⁻⁶ M of Terfenadine, a non-sedative anti-H1 active ingredient ofreference (Woodward and Munro 1982). Both products then possess "invitro" a very similar affinity for the H1 receptors in two differentspecies.

1.2 Studies on Isolated Ileon of Guinea Pigs

Successive concentrations of the compounds to be studied are testedagainst the same range of increasing concentrations of histamine whichact through its receptors of H1-type on the smooth muscular fibers fromthe wall of ileon, placed in a survival bath according to the techniquedetailedly described by FERRY and cowork (1970). The shift of therelationship between contracturing effect and concentration of histamineby the compound to be studied, stamps an anti-H1 activity. Under theseexperimental conditions, the compound of example III and Terfenadinebehaves in a very similar manner: no effect at 10⁻⁷ M, inhibition of thecompetitive type (ie. which allows to refind the whole action ofhistamine at a higher concentration) at 10⁻⁶ M and partiallyirreversible inhibition (ie. antagonizing a portion of the contractioninduced by Histamine whatever will be the concentration) at 10⁻⁵ M. Ifthe compound of example III appears to be slightly more active thanTerfenadine at 10⁻⁶ M, the opposite seems to be produced at 10⁻⁵ Mwithout that any of these tinges be significative between both products.

1.3 Studies on the Bronchospasm to Histamine in the Guinea Pigs

Inhalating an aerosol at 1%, of histamine (aqeuous solution in distilledwater, nebulization with a apparatus HOSPITAK) causes in the guineapigs, a bronchospasm which leads with immobilization of the animals ontheir own side. The time needed for the animals to lie down is measuredfor 5 minutes maximum. This period is called time of resistance and willbe longer when the animals have previously taken a compound endowed withanti H1-properties. Beyond the 300 seconds of observation, the animalsare said to be "proteted" of the broncho-constrictive action ofhistamine (Olsson 1971).

Intraperitoneally a fast total protection of all the animals subjectedto this test, has been obtained 30 minutes after administration of 10mg/kg of Terfenadine or the compound of example III, their activityappear to be again very similar. At 1 and 3 m/kg, Terfenadine and thecompound of example III remain poorly efficient under these experimentalconditions. Within this range of dosages the regression curve allow thecalculation of the efficient dosage at 50% (ED₅₀) for each of thecompounds: about 6.7 mg/kg for the compound of example III and about 7mg/kg for Terfenadine.

By oral way the single dosage of 10 mg/kg has been studied as a functionof time. The guinea pigs which have been given this dosage ofTerfenadine or of the compound of example III, are submitted to the testof Histamine aerosol from 30 mn, 1 hour, 2, 4, 6, 8, 12 and 24 hoursafter feeding (8 animals per product for each period). Terfenadine hasonly protected the animals for 4 hours whereas the animals which havereceived the compound of example III, have totally with stand to theeffects of inhaled histamine until 12 hours after administration of theanti-H1 compound. At the time 24 hours, the total protection (for morethan 5 minutes) can be still seen in 50% of the animals treated with thecompound of example III, which shows then a more longer duration ofaction than that of Terfenadine.

Conclusively, compound of example III distinguishes one self among thecompounds according to this invention as being carrier of a main anti-H1action of same intrinsic potency as Terfenadine, (CI₅₀) on the H1receptors, inhibition of the contraction of isolated ileon of guinea pigdue to Histamine, ED₅₀ by intraperitoneal way against bronchospasm dueto histamine in the guinea pigs but of higher duration of action afteradministration by oral way (bronchospasm due to Histamine in the guineapigs).

II--Search of Optional Side-Effects on the Central Nervous System (CNS)2.1 Measurements of Affinity for Various Receptors to Neuromediator

The compound of example III which has been selected on the basis of itsleading antiH1 activity, has been compared to two other anti-H1representatives of the two generations of this class of pharmacologicalagents. Mepyramine belongs to the first generation which displaysresidual sedative properties on the CNS. Terfenadine is the firstrepresentative of the second generation of anti-H1 compounds which ishenceforth deprived of side effects on the SNC (GARRISON 1990).

A broad range of membranar receptors of various rats organs has beentested according to the same principle than the H1 receptor under thefollowing conditions which are summarized:

Adenosine A1: cortex, 90 mn at 25° C. in 50 mM TRIS-ClH buffer (pH 7.7)against 1 nMol of [³ H] cyclohexyladenosine

Adenosine A2: striatum 60 mn at 25° in 50 mM TRIS-ClH buffer (pH 7.7)added with 50 nM cyclopentyladenosine, 10 mM Cl₂ Mg and 0.1 Unit/mladenosine-sesaminase against 4 nM of [³ H] NECA (5'-N-ethylcarboxamidoadenosine).

Muscarinic M1: pool of cortex, striatum and hypocampus, 60 mn at 25° C.in 10 mM PO₄ HNa₂ /PO₄ H₂ K buffer (pH 7.4) against 2 nM [³H]-pirenzepinc.

Muscarinic M2: pool of heart, ileon and cerebellus, 60 mn at 22° C. in50 mM TRIS-ClH buffer (pH 7.5) against 0.5 nM of [³ H]QNB(quinuclindinyl benzylate).

Central sites to benzodiazepines: whole brain, 90 mn at 0° C. in 50 mMTRIS-ClH buffer (pH 7.1) against 0.3 nM [³ H]-Flunitrazepam.

Peripheral sites to the benzodiazepines: Cortex 90 mn at 25° C. in 90 mMPO₄ HNa₂ /PO₄ H₂ K buffer, 81 mM ClNa and 9.5 nM ClK (pH 7.4) against 1nM [³ H]PK 11195.

GABA_(A) : whole brain 20 mn at 4° C., in 50 nM TRIS-ClH buffer (pH 7.2)added to 0.5%. TRITON X-100, against 5 nM [³ H] Muscimol.

GABA_(B) : Cerebellum, 10 mn at 22° C. in 50 mM TRIS-ClH buffer (pH 7.4)added to 1.2 mM SO⁴ Mg and 2.5 mM Cl₂ Ca, against 20 nM of [³ H]Baclofen.

Sigma receptors: whole brain, 2 hours at 22° C. in 50 mM TRIS-ClH buffer(pH 8) against 2 nM of [³ H] (+)3-PPP (3-(3-hydroxyphenyl)N-(1-propyl)piperidine).

As in the case of H1 receptor, the relationship between the percentagesof inhibition of the specific binding of the tritiated ligand as afunction of the increasing concentration of Mepyramine, Terfenadine orcompound of example III, allows the calculation the CI₅₀ for each of thecompounds for each of the receptors. The more weak is the CI₅₀, the morehigh is the affinity. When the inhibition is only partial, and doesallow only the calculation of a theoretical CI₅₀ higher than 10⁻⁵ M, itmay be considered that the affinity is very weak, indeed non existent.

The hereunder table summarizes the properties of the three studiedH1-antihistaminics.

    ______________________________________                                                                          Compound of                                 CI.sub.50 (M)                                                                             Mepyramine Terfenadine                                                                              example III                                 ______________________________________                                        Muscarinic M.sub.1                                                                        3,8 × 10.sup.-6                                                                    >10.sup.-5 >10.sup.-5                                  Muscarinic M.sub.2                                                                        3,5 × 10.sup.-6                                                                    >10.sup.-5 >10.sup.-5                                  Sigma receptor                                                                            5,9 × 10.sup.-7                                                                    >10.sup.-5 >10.sup.-5                                  Sites to                                                                      benzodiazepines:                                                              Central     >10.sup.-5 >10.sup.-5 >10.sup.-5                                  Peripheral  >10.sup.-5 >10.sup.-5 >10.sup.-5                                  Adenosine A.sub.1                                                                         >10.sup.-5 >10.sup.-5 >10.sup.-5                                  Adenosine A.sub.2                                                                         >10.sup.-5 >10.sup.-5 >10.sup.-5                                  GABA.sub.A  >10.sup.-5 >10.sup.-5 >10.sup.-5                                  GABA.sub.B  >10.sup.-5 >10.sup.-5 >10.sup.-5                                  ______________________________________                                    

Mepyramine shows a moderate but real affinity for the muscarinic M1 andM2 sites, about 1000 times weaker than that of Atropin, theanticholinergic agent of reference. Moreover a non negectible affinityfor the Sigma-receptor has been evidenced, of the order of 20 timesweaker than that of pentazocine, the reference ligand for this receptorsome of the effects of Mepyramine on the CNS may then found a functionalbasis in these residual non-H1affinities. At the contrary the absence ofaffinity which may be detected, under the same experimental conditionsunit the compound of example III to Terfenadine.

2.2 Study on the Behaviour in the Mice

The Irwin's test, modified according to Morpurgo's Technique (1971) hasbeen carried out to search optional alterations of the spontaneousbehaviour under the action of the compound of example III or of aH1-antihistaminic of the first generation Dexchloropheniramine, known toinduce some effects of drowsiness in the man. After administration byoral way, the mice have been kept under observation for 30 mn then havesubmitted to a seri. of simple test of behavioural screening after 30mn, 3 hours and 24 hours.

Dexchlorpheniramine at a dosage of 100 mg/kg has induced a hyperactivityand a slight irritability of after 30 mn, persisting at 3 hours anddisappearing after 24 hours. On the other side a mydriasis has beennoticed after 3 hours. The compound of example III did merely induce avery weak passivity in half of the animals having received the maximaltested dosage of 400 mg/kg, at the time 3 hours only. Moreover in asearch for a single maximal non-toxic dosage by the oral way in the samespecies, the mice which have received until 1000 mg/kg do not displayany clinical symptom. This is less fine than the Irvin's Test duringwhich the animals are handled and interact with the experimenter.

This lack of symptoms at high dosage is entirely of the opinion of anabsence of effects on CNS. Hyperactivity due to dexchlorpheniramine doesnot correspond to the sedative effect encountered in the main buthowever found expression in an influence on the cns. The mydriasisresults from an anticholinergic action at the ocular level, which ischaracteristic of Atropin by example.

2.3--Rota-Rod Test in the Mice

The principle of this test consists in chronometering the duration forwhich mice maintain itself on a rod rotating at a constant speed.Compounds which are endowed with sedative or myorelaxing or inhibitoryof the motor coordination, will induce a precocious fall, before 120seconds which are the maximals period of study. Beyond this time theanimals considered as possessing intact psychomotor capacities (Andrasiand cowork 1982, Ongini and cowork 1987). This test takes place 30 mnand 60 mn after administration. By oral way the compound of example IIIdid not alter the performances of the tested animals until the highesttested dosage of 100 mg/kg, in comparison with those recorded for mice,which receive only the vehicle of administration. Chlorpromazine, majorneuroleptic used as positive standard in the Rota-rod Test, caused thefall before the time granted, of 90% of the mice from the dosage of 4mg/kg by intraperitoneal way. In other supplemental assays, ketotifenefumarate--anti H₁ compound with long duration of action--has been shownto be able to decrease the performance of 25 to 35% of the treated micewith 50 mg/kg per oral way.

Conclusively compound of example III does not show noticeable effect onthe CNS under experimental situations where other H₁ anti-histaminicslead to various neurological alterations, hyperactivity, irritabilityand mydriasis with dexchlorpheniramine, changes in the performances inthe rota-rod test with ketotifene fumarate. Endly the profiles ofaffinity to the specific receptors of the main neurotransmitters allow adistinction between Mepyramine, antiH₁ of the first generation on oneside and Terfenadine and the compound of example III on the other side.These latter compounds do not possess any residual affinity on thereceptors, that let predict a profile similar to a non sedative type.

III--Conclusion of the Pharmacological Study

The compounds of this invention display at various degrees,anti-histaminic H₁ potentialities. Among them, the compound of exampleIII presents a pharmacological profile, close to that of Terfenadinewhich is characterized with a strength of activity similar in vitro aswell as in vivo and with a lack of side-effects on the CNS. Moreover thecompound of example III possesses a duration of action higher than thatof Terfenadine.

BIBLIOGRAPHICAL REFERENCES

ANDRAST F, BORVATH K, SINGER E, BERSENYL P, BORSY J, KENNESSEY A, TARRM, LANG T, KOROSI J and HAMORI T. Arzneim Forsch/Drug Res. 1987,37:1119-1124

GARISSON J. C in "The Pharmacologic Basis of Therapeutics" 8 st. edi. byGILMAN A. G, RALL T. W, NIES A. S and TAYLOR P. Pergamon Press Inc., NewYork 1990, pp 575-588

MORPURGO C. Arzneim. Forsch/Drug Res. 1971, 11:1727-1734

OLSSON O. A. T Acta Allergologica, 1971, 26:438-453

PERRY and the members of Department of Pharmacology of the University ofEDINBOURG in "Pharmacological experiments on isolated preparations"edited by E. S. LIVINGSTONE, EDINBOURG and LONDON, 1970: pp 58-87

WOODWARD J. K and MUNORO N. L Arzneim.Forsch/Drug Res. 1982,32:1154-1156

What is claimed is:
 1. A compound selected from the group consisting of a (4-substituted phenyl) 4-oxy 1 aminobutane of the formula ##STR41## wherein R₆ is selected from the group consisting of ##STR42## R₇ is selected from the group consisting of --COOH, tertbutyl and ##STR43## X is selected from the group consisting of >N-- and >CH--NH and R is a cyclic substituent selected from the group consisting of a) a xanthic derivative of the formula ##STR44## wherein R₁ and R₂ are individually selected from the group consisting of hydrogen and lower alkyl of 1 to 5 carbon atoms andR₃ is halobenzyl or ethoxyethyl and b) is benzimidazolic group of the formula ##STR45## wherein R₄ is hydrogen or halogen and R₅ is halobenzyl or ethoxyethyl and their non-toxic, pharmaceutically acceptable acid addition salts.
 2. A compound according to claim 1 having the formula I_(A) wherein R is a xanthyl selected from the group consisting of piperazinyl xanthines of the formula ##STR46## and the piperadyl amino xanthines of the formula ##STR47## wherein R₁, R₁ ' and R₂ are individually hydrogen or lower alkyl of 1 to 5 carbon atomsR₃ is halogenbenzyl group halobenzyl or ethoxyethyl and R₄ and R₅ are defined as in claim
 1. 3. A compound according to claim 1 having the formula I_(B) wherein R is a benzimidazolic radical, selected from the group consisting of piperazinyl benzimidazoles of formula I_(B') ##STR48## and the piperdylamino benzimidazoles of formula I_(B") ##STR49## wherein R₄, R₅, R₆ and R₇ have the definitions of claim
 1. 4. The acid addition salts of compound of formula I according to claim 1 with a mineral or organic acid.
 5. The optically-active isomers of a compound of formula I according to claim
 1. 6. The compounds of formula I' according to claim 1 ##STR50## wherein X and R are defined as defined in claim
 1. 7. The compounds according to claim 1 having the formula I_('A) ##STR51## wherein R₁ and R₂ have the definitions of claim
 1. 8. A compound according to claim 1 having the formula I'_(B) ##STR52## wherein R₄ and R₅ have the definitions of claim
 1. 9. A compound according to claim 1 which is 1,3-dimethyl 7-(4-fluorobenzyl) 8-[1-(4-tertbutylphenyl 4-hydroxy) butyl piperidyl-4 amino] xanthine.
 10. The compounds according to claim 1 which is 1,3-dimethyl 7-(4-fluorobenzyl) 8-[4-(4-tertbutylphenyl 4-hydroxybutyl) piperzinyl] xanthine.
 11. The compounds according to claim 1 which is 1-[4-fluorobenzyl) 2-[4-(4-tertbutylphenyl) 4-hydroxybutyl] piperazino benzimidazole.
 12. The compounds according to claim 1 which is (1-(4-fluorobenzyl) 2[(4-tertbutylphenyl 4-hydroxybutyl-4) piperidyl-4 amino] benzimidazole.
 13. A method of inducing anti-histamine H1 activity in warm-blooded animals comprising administering to said warm-blooded animals in need thereof an effective anti-histamine H1 activity inducing amount of a compound of claim
 1. 